Provost’s Chair Professor
Director, Singapore Institute for Neurotechnology (SINAPSE)
National University of Singapore
AsianScientist (Jul. 25, 2018) – Precision is paramount in medicine. No two patients are alike, and no combination of drugs works the same way in every individual. Professor Dean Ho knows this, and to grant greater credence to the word ‘precision’ in precision medicine, he is bringing artificial intelligence into the picture. With his CURATE.AI platform, he plans to enable clinicians to identify drug synergies and optimize combination therapies for individual patients.
Ho also performs research in translational nanomedicine, his specialty being nanodiamonds—diamonds with a size below 1 µm. By incorporating nanodiamonds into chemotherapy, contrast agents for biomedical imaging and even tooth fillings, he seeks to push the boundaries of nanomedicine and improve patient outcomes.
As the recently appointed Provost’s Chair Professor in the Department of Biomedical Engineering and Pharmacology and director of the Singapore Institute for Neurotechnology (SINAPSE) at the National University of Singapore (NUS), Ho hopes to bring more discoveries from bench to bedside. In this interview, Ho shares with Asian Scientist Magazine his journey going from student to researcher and inventor, and how clinicians and scientists can complement each other, just like the synergistic drugs he works with.
- What inspired or influenced you to become a biomedical engineer?
- A large part of your work revolves around nanodiamond platforms in medicine. Could you explain what this nanodiamond technology is about?
- Your team pioneered CURATE.AI—artificial intelligence that drives personalized and precision medicine. Can you tell us more about it?
- Besides project NDX and CURATE.AI, you are also the co-founder of KYAN Therapeutics. How does KYAN Therapeutics fit into your vision of personalized medicine?
- Besides the ones we have discussed, what other projects are you working on right now?
- What are the challenges that personalized medicine faces at the moment and how do you think they can be overcome?
- Now that you are here in Singapore as the Provost’s Chair Professor in the Department of Biomedical Engineering, what are your goals and what excites you most?
- What advice do you have for aspiring or young researchers?
I studied physiological science as an undergraduate, though I originally intended to go to law school afterwards. I even took the law school admission test, but a part of me always enjoyed science.
I like being able to make or develop something new. I also like engineering because it is multidisciplinary—it’s really exciting to be creating something new with people whose expertise ranges from basic biology to materials science, and even linguistics. So I kept deferring my law education, and never got around to actually doing it.
After I finished my PhD degree, I spent some time at Caltech (California Institute of technology) where the work became very translational. I learnt that it is a blend of fundamental and translational knowledge across multiple disciplines that will ultimately help people. Seeing the bigger picture there helped clarify my vision for the next decade of my academic career.
I still have a deep respect for the legal profession—I interact with attorneys all the time—but in the end, I think my calling was different.
We wanted an approach to deliver therapies in a way that would be safe and tolerable, with improved efficacy. Nanodiamonds are good materials for drug delivery because they are uniform and scalable—they are by-products of conventional mining and refining that can be rendered safe for biomedical applications.
Nanodiamonds can be functionalized to bind to virtually any drug, and two therapies emerged from this approach: nanodiamond-doxorubicin (NDX) for chemotherapy, and nanodiamond-gadolinium (ND-gadolinium) for imaging.
Doxorubicin is used in more than 90 percent of cancer treatments; it is a standard of care. With NDX, what we’re doing is adsorbing doxorubicin onto nanodiamonds, which makes doxorubicin safer, yet more potent. We showed that animals could survive NDX treatment even when a lethal dose of doxorubicin was used, and their tumors shrank substantially compared to the controls.
On the other hand, for ND-gadolinium, we covalently linked nanodiamonds to gadolinium, a contrast agent used in magnetic resonance imaging. We found that the nanodiamonds made gadolinium an order of magnitude brighter. As gadolinium is not well-tolerated in certain patients with kidney toxicity, we could give a patient less gadolinium but still be able to obtain the same contrast in imaging.
Ultimately, we want to move NDX and ND-gadolinium into the clinic. Right now, for NDX, we have one more safety study left. We have set up a roadmap of safety validation in rodent, canine and non-human primate models. Everything has been geared towards clinical trials and manufacturing, bridging fundamental research to the bedside.
Using drugs in combination is a cornerstone of many therapies, and the point is to achieve drug synergy. However, synergy is not the same as optimization. If somebody says a combination is synergistic, I need to know more. Usually, drug synergy is time- and dose-dependent, and patient-specific.
Synergy changes over time in the same person. People know this, but how can we address it? That is what CURATE.AI does. We have a way of uniquely correlating drug combinations with patient responses. This correlation allows us to create what we call a phenotypic map, which resembles a three-dimensional ‘mountain,’ with the peak being the optimum efficacy.
This ‘mountain’ changes constantly for the same person. Two drugs in this patient which are synergistic on Monday can become antagonistic on Friday, and our method can capture that to constantly modulate and optimize the treatment.
CURATE.AI implicitly accounts for patient heterogeneity, which means that it is broadly applicable to many different diseases. It can also continuously optimize the drug and the dose for the patient over the entire duration of care.
KYAN, to me, is not just a company. It embodies an ideal of giving people access to medicines that are way less expensive but perform at an unprecedented level. Drug development is often a lengthy, expensive and convoluted process. KYAN melts down this notion—we do it against the grain and it defies everything we know about drug development. Our core technologies enable novel, optimized drug combinations for everything ranging from oncology to metabolic diseases.
Our methodology is as such: we don’t just find an optimized combo in cells and then give it to an animal and see what happens, we will re-optimize the treatment for the animal. We can re-optimize the treatment in patients as well. We’ve carefully improved our approach over the past several years and our goal is to get the best medicines possible to patients at a thousandth of the development cost and five to eight years faster, while improving efficacy ten times or more. And we can do all of that with a scalable technology.
There was a time at UCLA (University of California, Los Angeles) when I had to get a root canal done. In this procedure, you need to pull out the dying nerve, clean out the infection and put in a filling material called gutta-percha (GP). GP is a non-structural polymer to help prevent re-infection.
I asked if it could benefit from being a stronger material. That was how nanodiamond gutta-percha (ND-GP) was conceived—we incorporated some nanodiamonds into the polymer mix and made GP a lot stronger.
We’ve received approval to start a clinical study with ND-GP, and this is classified as a phase-2/3 efficacy type of study for a new nanomaterial.
We need to single out what is possible with the technology that we are developing and what the needs are. Once we sieve through all of the hype, the reality sets in. There are a lot of preconceived notions in the field, and I think precision medicine needs to go through a phase where it lays everything on the table to see what is really implementable in the clinic.
I think that the challenge is about connecting with the other side, getting the clinicians to understand how this can be implemented with their daily standard-of-care routine and letting them know that we are not trying to radically change how care is done.
The real challenge after that is everything about compliance: patient compliance, both regulatory and behavioral. How can you validate this in such a way that a clinician will want to use it, that the patient will continue to use it after they start? That is the challenge for something like precision medicine.
What excites me is that the bulk of what we do now is patient-focused and patient-centered. We are always pairing our translational work with an understanding of the molecular basis of what we observe.
We do not shun blue-skies research, but from an ideological standpoint, our goal is to help bring together multiple disciplines to directly impact the patient. That is why I am here, I think we have good platforms, but the platforms are only as good as our ability to take it and develop something with it to help someone.
With the stakes at that level, you come to grips with the impact of the work and that is why we are here. It is to help others, patients and also colleagues that want to be a part of the team. It is about collegiality and leveraging the community. It is scary, once you are on the doorstep of taking whatever you have done to impact the patients of tomorrow.
I think that it is important for the researcher to appreciate the big picture of what they are embarking on. Today, their objective might be to synthesize a new biomaterial. The day after, their objective might be to test if it is safe.
Ultimately, know what your own end-points are for the research. If your goal is to get something into the clinic, start to engage with people that can help make that happen; make it a contact sport. Innovation is a contact sport!
Do not be afraid to interact with regulators. Regulations are there to help ensure that something that is new for the patient is safe and efficacious. It is the same goal as the person doing the research. See the big picture, know your end-points and then engage them directly to take it to that endpoint.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: University of California, Los Angeles.
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